The clinical study of neurogenetic diseases provides the context in which the goals of improved diagnosis and potential treatment modalities are identified. It both supports and stimulates the research necessary to achieve these objectives. Several new phenotypes have been recognized including a number of cases of the deficiency of hexosaminidase A presenting as motor neuron disease; glycerol kinase deficiency presenting as acidemia, stupor, and without mental retardation; biopterin deficiency presenting as familial dystonia; and a variety of cases of so-called Niemann-Pick disease, Type C. These later cases have permitted the demonstration that these phenotypes are not related to a defect in sphingomyelinase as previously believed. A number of rare phenotypes have also been identified including Tay-Sachs disease in a young non-Jewish child, 2 cases of juvenile Krabbe's disease, an unusual presentation of multiple sulfatase deficiency, an unusual case of San Filippo A disease, a case of arylsulfatase activator deficiency, a case of Menkes disease in a female infant, and several cases of acute neuronopathic Gaucher's disease. A large number of typical neurogenetic diseases have been confirmed by studies performed in this protocol. New diagnostic methods have been developed which permit the accurate diagnosis of Gaucher's and Niemann-Pick disease in a urine sample. Studies of chorionic villus samples (CVS) have allowed the prenatal diagnosis of a number of lysosomal storage diseases. We have developed an accurate method for biochemically distinguishing phenotypes of Gaucher's disease. This enables one to identify neurologic and non-neurologic phenotypes presymptomatically. A positive correlation has been found between the neuropathologic changes in Gaucher brain with the content of glucocerebroside. Finally, a clinical trial of enzyme replacement is being conducted in Gaucher's disease. The application of gene transfer to human disease is under consideration.